New use of melagatran

ABSTRACT

According to the invention there is provided the use of melagatran, or a pharmaceutically acceptable derivative or prodrug thereof, in the manufacture of a medicament for the treatment of inflammation.

FIELD OF THE INVENTION

[0001] This invention relates to a new use of the low molecular weightthrombin inhibitor, melagatran.

INTRODUCTION

[0002] Inflammation is a localised protective response elicited byinjury or destruction of tissues, which serves to destroy, dilute orsequester both the injurious agent and the injured tissue.

[0003] Inflammation may result from physical trauma, infection, somechronic diseases (e.g. psoriasis and autoimmune diseases, such asrheumatoid arthritis) and/or chemical and/or physiological reactions toexternal stimuli (e.g. as part of an allergic response). A complexseries of events may be involved, in which inflammatory mediatorsincrease blood flow and dilation of local blood vessels, resulting inredness and heat, the exudation of fluids, often resulting in localisedswelling, leukocytic migration into the inflamed area, and pain.

[0004] Current local and systemic treatments of inflammation, whichtreatments are employed typically when inflammation is an inappropriateresponse (e.g. in the treatment of autoimmune diseases), or isuncomfortable and/or inconvenient, include the administration of interalia non-steroidal anti-inflammatory agents (NSAIDs), opioid analgesicsand corticosteroids.

PRIOR ART

[0005] International patent application WO 94/29336 discloses a group ofcompounds that are useful as inhibitors of serine proteases, such asthrombin and/or kininogenases, such as kallikrein. Thethrombin-inhibiting compounds are thus indicated as anticoagulants, andthe kininogenase-inhibiting compounds as antiinflammatory agents.

[0006] One of the thrombin inhibiting compounds that is specificallydisclosed in WO 94/29336 is HOOC—CH₂—(R)Cgl-Aze-Pab-H, which is alsoknown as melagatran (see Example 1 of WO 94/29336, and the list ofabbreviations in this document). The use of melagatran in the inhibitionof kininogenases, and therefore in the treatment of inflammation, isneither mentioned nor suggested.

DISCLOSURE OF THE INVENTION

[0007] We have now found, surprisingly, that melagatran elicits anotable antiinflammatory effect, for example as described below, and maythus be used to treat inflammation in preferably mammalian, andespecially human, patients.

[0008] According to a first aspect of the invention there is providedthe use of melagatran, or a pharmaceutically acceptable derivative orprodrug thereof, in the manufacture of a medicament for the treatment ofinflammation.

[0009] The term “inflammation” will be understood by those skilled inthe art to include any condition characterised by a localised protectiveresponse elicited by injury or destruction of tissues resulting from anyof the causes mentioned hereinbefore, and which is manifest by heat,swelling, pain, redness, dilation of blood vessels and/or increasedblood flow, invasion of the affected area by white blood cells, loss offunction and/or any other symptoms known to be associated with theinflammatory condition. The term will thus be understood to includeinter alia acute, chronic, ulcerative, specific, allergic and necroticinflammation, as well as all other forms of inflammation known to thoseskilled in the art.

[0010] Melagatran, and derivatives and prodrugs thereof, may thus beused in the direct treatment of inflammation resulting from injury, fromviral or bacterial infection, or from a disease characterised byinflammation as one of its symptoms. Such diseases include autoimmunediseases, such as rheumatoid arthritis, psoriasis, allergy, asthma,rhinitis, pancreatitis, uticaria and inflammatory bowel syndrome.

[0011] However, melagatran, and derivatives and prodrugs thereof, arepreferably used in the treatment of inflammation in patients with, or atrisk of, a disease in which inhibition of thrombin is desired orrequired (see, for example, those listed in international patentapplication WO 97/23499), such as a thrombotic disease. Although thetreatment may be of patients whose inflammatory and thrombotic diseasesare unrelated, we prefer that the treatment is of a patient with athrombotic disease in which inflammation plays a part in triggeringcoagulation. For example, inflammation may arise in blood vessel wallsdue to the presence and/or the action of microbes and/or the agentsreleased thereby, physical damage, atheroscelorotic lesions and otherinflammation-inducing agents. It is preferred that melagatran, andderivatives and prodrugs thereof, are used in the treatment ofinflammation in patients having, or at risk of having, a thrombus.

[0012] For the avoidance of doubt, as used herein, the term “treatment”includes the therapeutic and/or prophylactic treatment of inflammation.

[0013] “Pharmaceutically acceptable derivatives” includes salts (e.g.pharmaceutically acceptable non-toxic organic or inorganic acid additionsalts) and solvates. The term “prodrug” of melagatran includes anycompound that, following oral or parenteral administration, ismetabolised in vivo to form melagatran (see, for example, internationalpatent application WO 97/23499). Preferred prodrugs are those of theformula R¹O₂C—CH₂—(R)Cgl-Aze-Pab-OH (see the list of abbreviations in WO97/23499), wherein R¹ represents linear or branched C₁₋₆ alkyl (e.g.C₁₋₄ alkyl, especially methyl, propyl and, particularly, ethyl) and theOH group replaces one of the amidino hydrogens in Pab.

[0014] Melagatran, and derivatives and prodrugs thereof, may beadministered for systemic delivery to the site of inflammation, or maybe administered for delivery directly (locally) to that site, usingappropriate means of administration that are known to the skilledperson.

[0015] Thus, in accordance with the invention, melagatran, andderivatives and prodrugs thereof, may be administered orally,intravenously, subcutaneously, buccally, rectally, dermally, nasally,tracheally, bronchially, topically, by any other parenteral route, orvia inhalation, in the form of a pharmaceutical preparation comprisingthe active ingredient in a pharmaceutically acceptable dosage form.Depending on the disorder, and the patient, to be treated, as well asthe route of administration, the compositions may be administered atvarying doses.

[0016] Preferred modes of delivery are systemic. For melagatran andderivatives thereof, preferred modes of administration are parenteral,more preferably intravenous, and especially subcutaneous. For prodrugsof melagatran, preferred modes of administration are oral.

[0017] In the therapeutic treatment of mammals, and especially humans,melagatran and derivatives and prodrugs thereof may be administeredalone, but will generally be administered as a pharmaceuticalformulation in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier, which may be selected with due regard to theintended route of administration and standard pharmaceutical practice.The preparation of suitable formulations for use in administeringmelagatran, derivatives and prodrugs thereof is described in theliterature, for example as described in inter alia international patentapplications WO 94/29336, WO 96/14084, WO 96/16671, WO 97/23499, WO97/39770, WO 97/45138, WO 98/16252, WO 99/27912 and WO 99/27913, thedisclosures in which documents are hereby incorporated by reference.Otherwise, the preparation of suitable formulations may be achievednon-inventively by the skilled person using routine techniques.

[0018] The amounts of melagatran, or derivative or prodrug thereof, inthe formulation will depend on the severity of the condition, and on thepatient, to be treated, as well as the compound(s) which is/areemployed, but may be determined non-inventively by the skilled person.

[0019] According to a further aspect of the invention there is provideda pharmaceutical formulation for use in the treatment of inflammationcomprising an effective amount of melagatran or a pharmaceuticallyacceptable derivative or prodrug thereof, in admixture with apharmaceutically acceptable adjuvant, diluent or carrier.

[0020] Melagatran, and derivatives and prodrugs thereof, may also becombined with other therapeutic agents that are useful in the treatmentof inflammation (e.g. NSAIDs, corticosteroids and analgesics), and/orother therapeutic agents that are useful in the treatment of a diseasecharacterised by inflammation as one of its symptoms. Melagatran, andderivatives and prodrugs thereof, may also be combined with othertherapeutic agents which, when administered, are known to give rise toinflammation as a side-effect. When melagatran, and derivatives andprodrugs thereof, are “combined” with other therapeutic agents in thisway, the active ingredients may be administered together in the sameformulation, or administered separately (simultaneously or sequentially)in different formulations.

[0021] Suitable doses of melagatran, prodrugs and derivatives thereof,in the therapeutic and/or prophylactic treatment of mammalian,especially human, patients are those which give a mean plasmaconcentration in the range 0.01 to 5 μmol/L. In any event, thephysician, or the skilled person, will be able to determine the actualdosage which will be most suitable for an individual patient, which islikely to vary with the age, weight and response of the particularpatient. The above dosages are exemplary of the average case; there can,of course, be individual instances where higher or lower dosage rangesare merited, and such are within the scope of this invention.

[0022] The skilled person will also appreciate that melagatran, or aderivative or prodrug thereof, may be administered in an appropriatedose on an “as required” basis (i.e. as needed or desired).

[0023] According to a further aspect of the invention there is provideda method of treating inflammation which comprises administering atherapeutically effective amount of melagatran, or a pharmaceuticallyacceptable derivative or prodrug thereof, to a patient in need of suchtreatment.

[0024] The use and method described herein may have the advantage that,in the treatment of inflammation, melagatran and derivatives andprodrugs thereof may not possess disadvantages of known antiinflammatoryagents. The use and method described herein may also have the advantagethat melagatran and derivatives and prodrugs thereof may be moreefficacious than, be less toxic than, have a broader range of activitythan, be more potent than, produce fewer side effects than, be moreeasily absorbed than, or that they may have other useful pharmacologicalproperties over, compounds known in the prior art for the treatment ofinflammation.

[0025] The invention is illustrated, but in no way limited, by thefollowing example.

EXAMPLE 1

[0026] Groups of five male Charles River CD rats in the weight range 180to 240 g were used. On their arrival, rats were housed in controlledenvironment rooms and fed a standard diet for at least one week beforeuse.

[0027] Rats were starved overnight before the test, although water wasgiven ad libitum. A mark was made on the ankle joint of each rat, theday before the test, to indicate where the foot volume was to bemeasured.

[0028] Compounds were made up in the appropriate vehicle for dosing viaeither the subcutaneous (s.c.), intravenous (i.v.) or oral (p.o.)routes. Melagatran was dosed in water (20 μmol/kg) when given p.o., andin saline, and in cyclodextrin (40%), when given s.c. (0.7 to 2μmol/kg). Drugs were administered in a dose volume of 5 mL/kg bodyweight for p.o. dosing or 1 to 2 mL/kg body weight for s.c. dosing.Control rats received the equivalent volume of vehicle.

[0029] A 1% solution of carrageenan in saline was prepared the day priorto the test. The carrageenan was suspended in saline and stirredvigorously on a magnetic stirrer for one hour. It was then stored at 4°C. until required. Thirty minutes after dosing, each rat was injecteds.c. in the plantar region of the left hind foot with 0.1 mL of 1%carrageenan.

[0030] To reduce both discomfort to the rat and variability in the test,rats were housed on wood chip bedding in solid bottom cages. The ratshad access to a solution of 5% glucose throughout the duration of thetest.

[0031] Foot volumes were measured using a water plethysmograph, theoutput being displayed using a digital voltmeter and recorded using aMac-Lab program. The plethysmograph was calibrated using blocks of 2 mLand 4 mL mass before the first, and after the last, measurement at eachtime point.

[0032] Foot volumes were measured before dosing and up to 6 hours afterthe sub-plantar injection of carrageenan. The increase in foot volumefor each rat was calculated using the difference between the individualfoot volume at time zero, and at the various time points. The inhibitionafforded by a treatment was expressed as a percentage inhibition of themean absolute increase in foot volume in created animals compared tocontrol animals. Indomethacin at 10 mg/kg p.o. was always included as aninternal standard. If indomethacin gave less than 30% inhibition at 4 hthen the test was considered invalid.

[0033] A number of standard compounds were tested and the results shownin Table 1. TABLE 1 % Inhibition after sub-plantar injection CompoundDose (route) 2 hours after 4 hours after Indomethacin   10 mg/kg (p.o.)43 50 Dexamethasone  0.3 mg/kg (p.o.) 51 96 Dexamethasone 0.03 mg/kg(p.o.) 47 74 Ibuprofen   10 mg/kg (p.o.) 22 26

[0034] When melagatran was administered orally (20 μmol/kg) in water 30minutes prior to the sub-plantar injection of carrageenan, it wasineffective in inhibiting paw oedema at up to 6 h post dosing. Whengiven s.c. in cyclodextrin (2 μmol/kg) a 29% inhibition of the oedemawas observed at 1 hour (Table 2). TABLE 2 % Inhibition after CompoundDose 1 hour 2 hours 3 hours 4 hours Indomethacin 10 mg/kg (p.o.) −5 5039 12 Melagatran 20 μmol/kg (p.o.) 14 17 −14 −2 Melagatran  2 μmol/kg(s.c.) 29 13 3 13

[0035] When melagatran was administered in saline at a dose of 24μmol/kg s.c., a 39% inhibition of the oedema was observed after 1 h(Table 3). TABLE 3 % Inhibition after Compound Dose 1 hour 2 hours 3hours 4 hours Indomethacin  10 mg/kg (p.o.) 15 2 29 18 Melagatran 2μmol/kg (s.c.) 39 8 2 −8

[0036] This finding was investigated further, with melagatran beingadministered in saline at doses of 0.7, 1.4 and 2 μmol/kg s.c., 30minutes prior to a sub-plantar injection of carrageenan, with paw oedemabeing measured at 1, 1.5, 2 and 3 hour time points. The results areshown in Table 4. TABLE 4 % Inhibition after Compound Dose 1 hour 1.5hours 2 hours 3 hours Melagatran 0.7 μmol/kg (s.c.) 39 −1 9 16Melagatran 1.4 μmol/kg (s.c.) 65 40 5 7 Melagatran 2.0 μmol/kg (s.c.) 7641 17 19

[0037] Due to the short duration of this experiment, indomethacincontrols were not included.

[0038] It can be seen clearly that melagatran inhibited paw oedema inboth a dose dependent, and time dependent, manner.

1. The use of melagatran, or a pharmaceutically acceptable derivative orprodrug thereof, in the manufacture of a medicament for the treatment ofinflammation.
 2. The use of melagatran, or a pharmaceutically acceptablederivative or prodrug thereof, in the manufacture of an antiinflammatorymedicament.
 3. A method of treatment of inflammation which comprisesadministering a therapeutically effective amount of melagatran, or apharmaceutically acceptable derivative or prodrug thereof, to a patientin need of such treatment.
 4. A pharmaceutical formulation for use inthe treatment of inflammation comprising an effective amount ofmelagatran, or a pharmaceutically acceptable derivative or prodrugthereof.
 5. Use of melagatran, or a pharmaceutically acceptablederivative or prodrug thereof, for the treatment of inflammation byadministering melagatran, or a pharmaceutically acceptable derivative orprodrug thereof, to a patient.
 6. The use of melagatran, or apharmaceutically acceptable derivative or prodrug thereof, in thetreatment of inflammation.
 7. A use, method or formulation as claimed inany one of claims 1 to 6 (as appropriate), wherein the treatment is ofinflammation in patients with, or at risk of, a disease in whichinhibition of thrombin is desired or required.
 8. A use, method orformulation as claimed in claim 7, wherein the disease is one in whichinflammation plays a part in triggering coagulation.
 9. A use, method orformulation as claimed in claim 7 or claim 8, wherein the patient has,or is at risk of, a thrombus.
 10. A use, method or formulation asclaimed in any one of the preceding claims, wherein the prodrug is theformula R¹O₂C—CH₂—(R)Cgl-Aze-Pab-OH wherein R¹ represents linear orbranched C₁₋₆ alkyl and the OH group replaces one of the amidinohydrogens in Pab.
 11. A use, method or formulation as claimed in claim10, wherein R¹ represents methyl, ethyl or propyl.